This invention relates to a method of treatment of breast and endometrial cancer in susceptible warm-blooded animals including humans and in particular to combination therapy involving administration of anti-estrogens in combination with other inhibitors of hormone production, inhibitors of hormone functions and/or in combination with other hormones.
Various investigators have been studying hormone-dependent breast and endometrial cancer. A known form of endocrine therapy in premenopausal women is castration most commonly performed by surgery or irradiation, two procedures giving irreversible castration. Recently, a reversible form of castration has been achieved by utilizing Luteinizing Hormone Releasing Hormone agonists ("LHRH agonists") which, following inhibition of secretion of bioactive Luteinizing Hormone ("LH") by the pituitary gland, decrease serum estrogens to castrated levels (Nicholson et al., Brit. J. Cancer 39, 268-273, 1979).
Several studies show that treatment of premenopausal breast cancer patients with LHRH agonists induces responses comparable to those achieved with other forms of castration (Klijn et al., J. Steroid Biochem. 20 1381, 1984; Manni et al., Endocr. Rev. 7: 89-94; 1986). Beneficial effects of treatment with LHRH agonist have also been observed in post-menopausal women (Nicholson et al., J. Ster. Biochem. 23, 843-848, 1985).
A. V. Schally et al., Cancer Treatment Reports, 68 (No. 1) 281-289 (1984), summarize the results of animal and clinical studies on growth inhibition of hormone-dependent mammary and prostate tumors by use of analogues of luteinizing hormone-releasing hormone, the so-called LHRH agonists and suggest that LHRH analogs and/or antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Proc. Natl. Acad. Sci. U.S.A. 80, 1459-1462 (1983) disclose reduction of estrogen-dependent memory tumors in rats and mice by use of an LHRH agonist (D-Trp.sup.6 ]LHRH or of two specific antagonists.
In U.S. Pat. No. 4,071,622, it is disclosed that use of certain LHRH agonists causes regression of DMBA-induced mammary carcinoma in rats.
U.S. Pat. No. 4,775,660 relates to the treatment of female breast cancer by use of a combination therapy comprising administering an antiandrogen and an antiestrogen to a female after the hormone output of her ovaries has been blocked by chemical or surgical means.
U.S. Pat. No. 4,775,661 relates to the treatment of female breast cancer by use of a therapy comprising administering to a female after the hormone output of her ovaries has been blocked by chemical or surgical means an antiandrogen and optionally an inhibitor of sex steroid biosynthesis.
U.S. Pat. No. 4,760,053 describes a treatment of selected sex steroid dependent cancers which combines an LHRH agonist and/or an antiandrogen and/or an antiestrogen and/or at least one inhibitor of sex steroid biosynthesis.
In U.S. Pat. No. 4,472,382, it is disclosed that prostatic adenocarcinoma, benign prostatic hypertrophy and hormone-dependent mammary tumors may be treated with various LH-RH agonists and that prostrate adenocarcinoma and benign hypertrophy may be treated by use of various LHRH agonists and an antiandrogen. However, there is no suggestion or disclosure of the present invention.
Some clinical improvement in premenopausal women with breast cancer by use of the two LHRH agonists, Buserelin and Leuprolide, is also reported by H. A. Harvey et al. "LH-RH analogs in the treatment of human breast cancer", LHRH and its Analogs--A new Class of contraceptive and therapeutic Agents (B. H. Vickery and J. J. Nestor, Jr., and E. S. E. Hafez, eds) Lancaster, MTP Press, (1984) and the J. G. M. Klijn et al, "Treatment with luteinizing hormone-relating hormone analogue (Buserelin) in premenopausal patients with metastatic breast cancer", Lancet 1, 1213-1216 (1982).
Androgen receptors have been demonstrated in human breast cancer samples (Engelsman et al., Brit. J. Cancer 30, 177, 1975; Lippman et al., Cancer 38, 868-874, 1976; Maass et al., J. Steroid Biochem. 6, 743-749, 1975) and in human breast cancer cell lines including MCF-7 cells (Lippman et al., Cancer Res. 36, 4610-4618, 1976). Recent reports have indicated that androgen receptors may add to the selective power of estrogen receptors (ER) or even supplant ER towards predicting response to endocrine therapy (Bryan et al., Cancer 54, 2436-2440, 1984; Teulings et al., Cancer Res. 40: 2557-2561, 1980).
The first androgen successfully used in the treatment of advanced breast cancer is testosterone propionate (Nathanson, Rec. Progr. Horm. Res. 1, 261-291, 1947). Many studies subsequently confirmed the beneficial effect of androgens on breast cancer (Adair, Surg. Gynecol. Obstet. 84, 719-722, 1947; Alan and Herrman, Ann. Surg. 123, 1023-1035, 1946; Adair et al., JAMA 140, 1193-2000, 1949). These initial results stimulated cooperative studies on the effect of testosterone propionate and DES which were both found to be effective in producing objective remissions. (Subcommittee on Steroids and Cancer of the Committee on Research of the Council on Pharmacy and Chemistry of the Am. Med. Association followed by the Cooperative Breast Cancer Group under the Cancer Chemotherapy National Service Center of the NCI who found that testosterone propionate improved remission rate and duration, quality of life and survival (Cooperative Breast Cancer Group, JAMA 188, 1069-1072, 1964).
A response rate of 48% (13 of 27 patients) was observed in postmenopausal women who received the long-acting androgen methonolone enanthate (Kennedy et al., Cancer 21, 197-201, 1967). The median duration of survival was four times longer in the responders as compared to the non-responder group (27 versus 7.5 months). A large number of studies have demonstrated that androgen induce remission in 20 to 40% of women with metastatic breast cancer (Kennedy, Hormone Therapy in Cancer. Geriatrics 25, 106-112, 1970; Goldenberg et al., JAMA 223, 1267-1268, 1973).
The combination Fluoxymesterone and Tamoxifen has been shown to be superior to Tamoxifen alone. In fact, complete responses (CR) were seen only in the combination arm while 32% showed partial response (PR) in the combination arm versus only 15% in the monotherapy arm. In addition, there were only 25% non-responders in the combination therapy arm versus 50% in the patients who received TAM alone (Tormey et al., Ann. Int. Med. 98, 139-144, 1983). Moreover, the median time from onset of therapy to treatment failure was longer with Fluoxymesterone+Tamoxifen (180 days) compared to the Tamoxifen arm alone (64 days). There was a tendency for improved survival in the combination therapy arm (380 versus 330 days).
The independent beneficial effect of an antiestrogen combined with an androgen is suggested by the report that patients who did not respond to Tamoxifen could respond to Fluoxymesterone and vice versa. Moreover, patients treated with Tamoxifen and crossing over to Fluoxymesterone survived longer than the reverse regimen (Tormey et al., Ann. Int. Med. 98, 139-144, 1983). Recent in vitro studies compose the relative anti-proliferative activities of an antiestrogen and an androgen on the growth of the estrogen-sensitive human mammary carcinoma cell line ZR-75-1 (Poulin et al. "Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line", Breast Cancer Res. Treatm. 12, 213-225, 1989a).
A response rate of 39% with an average duration of 11 months has recently been observed in a group of 33 postmenopausal women who previously failed or did not respond to Tamoxifen (Manni et al., Cancer 48: 2507-2509, 1981) upon treatment with fluoxymesterone (Halostatin) (10 mg, b.i.d). Of these women, 17 has also undergone hypophysectomy. There was no difference in the response rate to Fluoxymesterone in patients who had previously responded to Tamoxifen and in those who had failed. Of the 17 patients who had failed to both Tamoxifen and hypophysectomy, 7 responded to Fluoxymesterone for an average duration of 10 months. Among these, two had not responded to either Tamoxifen and hypophysectomy.
Since testosterone propionate had beneficial effects in both pre- and postmenopausal women (Adair et al., J. Am. Med. Ass. 15: 1193-100; 1949), it indicates that in addition to inhibiting gonadotropin secretion, the androgen exerts a direct inhibitory effect on cancer growth.
As mentioned above, Poulin et al. (Breast Cancer Res. Treatm. 12, 213-225, 1989a) have found that the growth of ZR-75-1 human breast carcinoma cells is inhibited by androgens, the inhibitory effect of androgens being additive to that of an antiestrogen. The inhibitory effect of androgens on the growth of human breast carcinoma cells ZR-75-1 has also been observed in vivo in nude mice.
Many clinical trails have shown the benefits of medroxyprogesterone acetate ("MPA") in breast cancer therapy (Cavalli et al., J. Clin. Oncol. 2, 414, 1984; Van Veelen et al., Cancer 58, 713, 1986; Johnson et al., Brit. J. Cancer 50, 363, 1984; Rabustelli della Cuna, G. Comprehensive guide to the therapeutic use of medroxyprogesterone acetate in oncology, Famitalia Carlo Erba, S.P.A., 1987).
Poulin et al. "Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells", Breast Cancer Res. Treatm. 1989b, in press) have recently found that the inhibitory effect of medroxyprogesterone acetate (MPA) on the growth of the human ZR-75-1 breast cancer cells is mainly due to the androgenic properties of the compound. The androgenic properties of MPA have been clearly demonstrated in other systems (Labrie, C. et al., J. Steroid Biochem. 28: 379-384, 1987; Luthy et al., J. Steroid Biochem. 31: 845-852, 1988; Plante et al., J. Steroid Biochem., 31, 61-64, 1988). Other synthetic progestins have also been shown to possess, in addition to their progesterone-like activity, various degrees of androgenic activity (Labrie et al., Fertil, Steril. 31, 29-34, 1979; Poyet and Labrie, The Prostate 9, 237-246, 1986; Labrie, C. et al., J. Steroid Biochem. 28: 379-384, 1987; Luthy et al., J. Steroid Biochem. 31: 845-852, 1988; Plants et al., J. Steroid Biochem. 31, 61-64, 1988).
Poulin et al. "Inhibition of estrogen-dependent cell proliferation by the synthetic progestin R5020 and antagonism of progestin action by insulin in ZR-75-1 human breast cancer cells", Breast Cancer Res. Treatm., 1989c, in press) have observed that 17,21-dimethyl-19-non-4,9-pregnadiene-3,20-dione ("R5020, promegestone") and progesterone itself can inhibit the growth of the human breast cancer cell line ZR-75-1 by an action mediated by the progesterone receptor. R5020 has been found to inhibit the growth of normal human breast cancer cells in culture in the presence as well as in the absence of E.sub.2 (Gompel et al., J. Clin. Endocrinol. Metab. 63, 1174-1180, 1986).
H. Mouridsen et al., Cancer Treatm. Rev. 5, 131-141, (1978), disclose that Tamoxifen, an antiestrogen, is effective in remission of advanced breast cancer in about 30% of the women patients treated.
J. G. M. Klijn et al., (J. Steroid Biochem., 20 (No. 6B), 1381 (1984), disclosed the combined use of the antiestrogen, Tamoxifen, and the LHRH agonist, Buserelin, for treatment of breast cancer is known but objective remission of such cancers remains low (35%).
Various steroids have been described as irreversible aromatase inhibitors, including 4-hydroxy-4-androstene-3,17-dione (Brodie et al., Steroids 38: 693-702, 1981; Covey and Hood, Cancer Res. 42; Suppl. 3327s-3333s, 1982), androsta-4,6-triene-3,17-dione (Covey and Hood, Endocrinology 108, 1597-1599, 1981), MDL 18962 (Johnston et al., Endocrinology 115, 776-785, 1984), SH 489 (Henderson et al., J. Steroid Biochem. 24, 303-306, 1986) and 6-methylenandrosta-1,4-diene-3,17-dione ("FCE 24304") (Giudici et al., J. Steroid Biochem. 30: 391-394, 1988).
Huggins and Bergenstal (Cancer Res. 12, 134-141, 1952) have observed that adrenalectomy could induce remission in breast cancer patients who had failed after castration. Treatment of advanced breast cancer with aminoglutethimide after therapy with the antiestrogen Tamoxifen is disclosed by A. V. Buzdar et al. Cancer 50, 1708-1712 (1982).
High doses of ketoconazole can inhibit 17.alpha.-hydroxylase and C17-20-lyase (Santen et al., J. Clin. Endocrinol. Metab. 57, 732-736, 1983) while 16-methylene estrone can inhibit the 17.beta.-HSD step (Thomas et al., J. Biol. Chem. 258, 11500-11503, 1983).
Trilostane and epostane have been described as inhibitors of 3.beta.-hydroxy-steroid dehydrogenase activity (Ernshaw et al., Clin. Endocrinol, 21, 13-21, 1984; Robinson et al., J. Steroid Biochem. 21, 601-605, 1984; Lambert et al., Ann. Clin. Biochem. 23, 225-229, 1986; Potts et al., Steroids 32, 257-267, 1978) and have been successfully used for the treatment of breast cancer in combination with corticosteroids (Beardwell et al., Cancer Chemother. Pharmacol. 10: 158-160, 1983; Williams et al., Cancer Treat. Rep. 71, 1197-1201, 1987).
4-MA, (17.beta.-N,N-diethylcarbamoyl-4-methyl-4-aza-5.alpha.-androstan-3-one) has been found to inhibit 3.beta.-hydroxysteroid dehydrogenase activity in granulosa cells (Chan et al., Biochem. Biophys. Res. Commun. 144, 166-171, 1987). Epostane has been shown to inhibit 3.beta.-hydroxysteroid dehydrogenase activity in pregnant goats (Taylor, J. Endocrinol. 113, 489-493, 1987).
A synthetic androgen, methyltrienolone has been reported to inhibit the growth of endometrial carcinoma cells in culture (Centola, Cancer Res. 45: 6264-6267, 1985). Medroxyprogesterone acetate is successfully used for the treatment of endometrial cancer (Ayoub et al., Gynecol. Oncol. 31(2): 327-337, 1988).
Prolactin and growth hormone have been shown to stimulate colony formation of the NMU rat mammary tumor cultured in vitro in the soft agar clonogenic assay (Manni and Wright, J. Natl Cancer Inst. 74, 941-944, 1985).
Prolactin is known to play a role in stimulating carcinoma in experimental animals, especially mammary carcinoma induced in the rate by dimethylbenz(a)anthracene (DMBA) (Welch et al., Cancer Res. 30, 1024-1029 1970). A study of 30 women suffering from breast cancer showed that 10 became pain-free upon treatment with L-Dopa, an inhibitor of prolactin secretion (Minton, Cancer 33, 358-363, 1974). In these 10 women, there were objective and subjective signs of tumor control.
A problem with prior art treatments is a lack of effective simultaneous control of both beneficial and detrimental hormones. Moreover, effective control of detrimental hormones (i.e. those hormones which may stimulate tumor growth) often requires closing down a plurality of pathways. Prior art treatments have tended to foreclose only particular synthetic pathways, leaving other pathways available for formation of the undesired hormone. Other treatments have attempted to block the activity of detrimental hormones such as estrogens. However, because such blocking is difficult to completely achieve, the formation of the estrogens, together with incomplete blocking, enables some estrogens to bind and undesirably activate receptors. This necessarily diminishes the effectiveness of treatment.